A substantial proportion of individuals with epilepsy suffer from depression but the mechanisms underlying epilepsy-associated depression (EAD) are not understood. Such a level of understanding is essential for designing new modalities for the treatment and prevention of EAD. Our previous work showed that animals that develop epilepsy as result of status epilepticus (SE) develop behavioral symptoms of despair and hopelessness. These animals show decreased evoked serotonin levels in cortex and hippocampus but the cause of decreased serotonin levels in epileptic animals is still not understood. The excitatory projection from the medial prefrontal cortex (mPFC) to the RN plays an essential role in the top-down control of serotonin release, and activating this system can rescue depression-related behaviors. We therefore hypothesize that this prefrontal input is weakened in animals with epilepsy and that optogenetic methods can be used increase excitatory drive from the remaining prefrontal inputs to normalize serotonin levels and treat EAD. The main goal of this proposal is to explore optogenetic stimulation of long-range inputs into serotonergic RN as a novel therapeutic proof-of-principle approach for effective management of EAD. We will use cutting edge in-vivo optogenetic techniques, behavioral studies, and electrophysiology to find convergent evidence for the role of long-range projections in depression in epilepsy. Specifically we will test the hypothesis that EAD is characterized by the diminished excitatory drive from mPFC into the RN and that normalizing the function of the mPFC-RN pathway exerts antidepressant effects in animals with chronic epilepsy and concurrent depression.

Public Health Relevance

A substantial proportion of individuals with epilepsy suffer from depression, but the cause of depression in these individuals is not understood. Epilepsy-associated depression may be caused to decreased connections between prefrontal cortex and the serotonergic raphe nucleus. This project will determine whether selectively activating this projection can be used to treat depression in epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS089396-01
Application #
8755190
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Whittemore, Vicky R
Project Start
2014-07-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Kumar, Udaya; Medel-Matus, Jesus-Servando; Redwine, Hannah M et al. (2016) Effects of selective serotonin and norepinephrine reuptake inhibitors on depressive- and impulsive-like behaviors and on monoamine transmission in experimental temporal lobe epilepsy. Epilepsia 57:506-15
Hagen, Eunice; Shprung, Dana; Minakova, Elena et al. (2015) Autism-Like Behavior in BTBR Mice Is Improved by Electroconvulsive Therapy. Neurotherapeutics 12:657-66
Washington 3rd, James; Kumar, Udaya; Medel-Matus, Jesus-Servando et al. (2015) Cytokine-dependent bidirectional connection between impaired social behavior and susceptibility to seizures associated with maternal immune activation in mice. Epilepsy Behav 50:40-5